The real-world observational study demonstrated the advantages of high-neutralizing antibody titer (> 1:320) convalescent plasma therapy for severe COVID-19. Compared with standard care, there was lower all-cause mortality (15%) in the CPT arm with a low HR by univariate and multivariate analysis. Survival analysis showed that CPT resulted in a significantly higher survival rate than standard care. The median survival time with standard care was 7 days after admission. Nevertheless, the standard of care group tended to have lower oxygen saturation on admission and more elderly patients than the CPT-treated group.
Our study demonstrated that high titer (> 1:320) CPT reduced 14- and 28-day mortality from severe COVID-19, reducing the duration of supplemental oxygen and decreasing high-flow oxygen requirements. The CPT group improved the WHO clinical progression scale on day 5 and the radiologic parameter on day 7. A recent study showed high-titer (1:80–1:320) CCP transfused within 3 days of COVID-19 diagnosis related to decreasing mechanical ventilation and mortality [2, 20, 21]. Similarly, an RCT showed a 57% reduction in mortality rate with high-titer (> 1:160) CPT (13%) compared with control (25%) (odds ratio 0.43; p < 0.001) . Our findings correlated with the recent study that demonstrated the relationship between reduced mortality and early transfusion time, and high antibody CPT provided favorable efficacy in hospitalized patients’ treatment [20, 21].
In contrast, the CONCOR-1 study did not show a benefit of CCP in reducing mortality, intensive care unit admission, length of stay, or risk of endotracheal intubation. The RECAP-MAP study did not demonstrate that CPT was associated with a difference in mortality and the number of organ-support-free days compared with usual care. However, the PRNT50 titer of CCP transfused in the CONCOR-1, RECAP-MAP study was only 160 IQR (80, 320) and ≥ 1:160, respectively, lower than our study. [22, 23].
Even though the data from the RECOVERY trial showed 1:300 titer of CPT could not show a discrepancy in mortality from the standard of care. 29.4% of CPT patients were hospitalized in the critical care unit on admission day. This might imply that more severe cases and prolonged symptoms before CCP transfusion (8 days) might have affected the mortality and clinical outcomes compared with the duration of symptoms before transfused CCP in our study (5.5 days) . However, our study could not show that CPT reduced overall oxygen supplemental, including low or high-flow oxygen, invasive mechanical ventilation, or extra-corporeal membrane oxygenation at 28 days like a recent multicenter study .
However, a recent RCT failed to show a difference between CPT and usual care; low neutralizing antibodies of CCP might not be effective enough to demonstrate benefit in reducing mortality [9, 10]. In a study in patients with COVID-19-related symptoms for 10 days and classified as moderate, severe, and critical, the PRNT50 titer of CCP was 160 (IQR 80–640) and did not demonstrate an advantage in survival improvement, course of illnesses, or viral clearance . The challenge of high-titer CPT early in the course of the disease remains an interesting issue.
A study in the Netherlands revealed that mortality with CPT with neutralizing antibody titer ≥ 1:80 was non-statistically significantly lower than usual care, which might have been because of the low-titer CPT .
Another study demonstrated that high-titer neutralizing antibody CPT demonstrated equivocal results in the rate of supplemental oxygen from baseline characteristics of severe COVID-19 patients, which did not correlate with very low supplemental oxygen requirement in the primary outcome . A study in a respiratory care unit (RCU) revealed that CCP from donors with a high immunoglobulin G antibody titer level had more favorable outcomes than those with a low titer . The study in severely ill patients transfused with mainly high neutralizing antibody titers of 1:640 within 3 days after COVID-19 was diagnosed led to successful weaning from oxygenation support after CPT within 3 days. Moreover, the radiologic improvement was demonstrated within 7 days. CPT within 14 days provides more favorable outcomes than after 14 days [28, 29].
Our study highlighted the benefit of higher neutralizing antibody level CPT in those with a shorter duration from onset of symptoms and earlier developed severe COVID-19 than other studies.
In our study, 15.3% of patients receiving CPT died from severe COVID-19 at 14 and 28-day, and one died from severe COVID-19 pneumonia with gastrointestinal bleeding and hyperglycemia. Almost all death cases from severe COVID-19 had delayed receiving CPT after 5 days of admission due to the physician waiting for RdRp inhibitor effect and had ≥ 2 comorbidities such as elderly, uncontrolled diabetes, and obesity. Other CPT studies have demonstrated that early CPT within 3 days after hypoxemia results in the greatest advantage.
According to many studies and meta-analyses, CPT might be an unsuitable treatment in late severe or critical COVID-19 owing to the pathophysiology that neutralizing antibodies might protect the SARS-CoV-2 from invading respiratory epithelial in early-stage of SARS-COV-2 infection .
The extended length of stay in the CCP receiving group (10 days) reflected the rapid deterioration, early death, and shortening stay in the standard of care group (7 days). The study in Mexico reported a prolonged stay of 22.5 days after CCP transfusion, in contrast to the 10 days in our study: the shorter stay might suggest the benefit of CPT in early developed severe COVID-19 . Interestingly, although the invasive mechanical ventilation receiving rate was 85% in both groups, the successful weaning oxygenation support was 84.6% in the CPT group, much more than 14.5% in the control group. Moreover, Almost all CPT patients had clinical improvement within 7 days after CCP transfusion.
Our study supported the favorable CPT evidence in COVID-19, especially in those who earlier developed severe COVID-19. The CPT within 9 days after admission showed a benefit of 3.4% absolute risk reduction for individuals with risk factors for disease progression or vaccination status. The outpatient study demonstrated that early CPT reduced disease progression risk, leading to hospitalization . Although the potential benefit of early high-titer CPT in mildly ill older adults demonstrated reduced deterioration to severe COVID-19, our data supported the benefit of CPT in a study in older adults and individuals with severe COVID-19 with or without comorbidities .
Although some CPT studies report cases of anaphylactic shock , our study demonstrated no serious adverse events, transfusion-related acute lung injury, or transfusion-associated circulatory overload. One patient developed a transfusion-related minor allergic reaction, which spontaneously recovered.
The limitation of our study is the real-world retrospective observational study in nature. The CPT and standard care groups were cared for by different groups of clinicians, albeit concurrently, during the Delta variant epidemic in Thailand. The lack of declared immunization status in both donor and recipient, previous SARS-CoV-2 infection, previous treatment or inadequate treatment data before admission, the patients' immunogenicity, or neutralizing antibodies testing to spike protein of SARS-CoV-2 in our study might influence the interpreting of the clinical outcomes from CPT. All patients who received RdRp inhibitor due to Thai standard treatment guidelines might affect the outcome. Resource limitations characteristic of a community hospital setting meant that essential biomarkers such as high-sensitivity C-reactive protein or ferritin to detect clinical deterioration were unavailable. However, hypoxemia in severe COVID-19 indicated deterioration and reflects worsening severity. The lack of virologic and immunologic studies is also a limitation of our study.